title: IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells.
abstract: OBJECTIVE
  Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified.
  
  
  RESULTS
  1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect.
  
  
  CONCLUSIONS
  We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine.
authors.affiliation: Department of Neurology and Experimental Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Neeb
authors.forename: Peter
authors.initials: P
authors.lastname: Hellen
authors.forename: Carsten
authors.initials: C
authors.lastname: Boehnke
authors.forename: Jan
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Sigrid
authors.initials: S
authors.lastname: Schuh-Hofer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Uwe
authors.initials: U
authors.lastname: Reuter
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012668:Trigeminal Ganglion / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone